This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. It is well documented that inherited genetic traits play a critical role in individual susceptibility to tobacco-related cancers. Recently, several sequence variations (polymorphisms) coding for amino acid changes in DNA repair genes have been identified;however, little is known about their effects on cellular responses to genetic damage induced by exposure to tobacco smoke. We will investigate the roles of polymorphisms in several DNA repair genes (e.g. XRCC1, XRCC3, and XPD) involved in three major DNA repair pathways), while taking into consideration the role of influential polymorphisms in genes for biotransformation enzymes. We hypothesize that inherited polymorphisms coding for amino acid changes in DNA repair genes affect the efficiency of DNA repair, thus leading to increased accumulation of genetic damage in response to smoking at both the chromosomal and gene levels. We will test our hypothesis in a population of 400 non-symptomatic smokers and 400 healthy non-smokers. We will use biomarkers of exposure (cotinine levels in plasma) and of biological effects (cytogenetic end points and somatic cell gene mutations) to investigate the influence of DNA repair polymorphisms on the induction of genetic damage. In addition, in controlled in vitro experiments, we will determine the roles of these polymorphisms in the induction of genetic damage in cultured cells exposed to model tobacco carcinogens. The study will also have significant implications for understanding the role of these polymorphisms in smoking-associated cancer risk. Knowledge gained from the study is critical for providing new mechanistic explanations for differential susceptibility to tobacco smoking.